Our Science – Zhang Website

Ying E. Zhang, Ph.D.

Laboratory of Cellular and Molecular Biology Senior Investigator Building 37, Room 2066 37 Convent Dr., MSC 4256 Bethesda, MD 20892-4256 Phone:   301-496-6454 Fax:   301-496-8479 E-Mail:   yingz@helix.nih.gov

Biography

Dr. Ying Zhang received her B.S. degree in Chemistry and M.S. degree in Biochemistry from Beijing University, China. She obtained her Ph.D. degree from University of Wisconsin-Madison in 1995. She carried out her postdoctoral training in the laboratory of Dr. Rik Derynck at University of California, San Francisco. She was an assistant research investigator in the Department of Growth and Development at UCSF before joining the Laboratory of Cellular and Molecular Biology in 2000.

Research

Molecular mechanisms of TGF-beta signaling pathway

Members of the transforming growth factor-beta (TGF-beta) family of peptide growth factors, which include TGF-beta, bone morphogenetic proteins (BMPs) and activins, regulate a broad range of cellular processes from cell growth and differentiation to apoptosis. The signaling responses to TGF-beta and other family members are mediated by a heteromeric complex of two types of transmembrane serine/threonine kinase receptors at the cell surface, and their intracellular substrates, the Smad proteins. To date, genetic or epigenetic alterations of different components of the TGF-beta signaling pathway have been reported in a number of human developmental or hyper-proliferative disorders and in various forms of cancers. Our research has focused on three aspects of TGF-beta signaling in an attempt to gain further appreciation of its regulation, mechanisms of action and function in development and tumorigenesis.

The first of these is to understand the role of the ubiquitin-proteasome system in modulating TGF-beta signaling. We, and others, have previously identified two Smad ubiquitin regulatory factors (Smurfs) of the HECT domain-containing ubiquitin ligase family and shown that Smurf1 and Smurf2 have the ability to interact directly with Smad1 and Smad5 of the BMP pathway and mediate their degradation. To address the physiological significance of Smurfs in TGF-beta signaling, we have generated mice lacking either Smurf1 or Smurf2, and reported that Smurf1-deficient mice are perinatally normal but exhibit an age-dependent increase of bone mass due to enhanced osteoblast activity and increased responsiveness to BMP. Surprisingly, this skeletal abnormality is not caused by alteration in Smad-mediated TGF-beta or BMP signaling. Instead, loss of Smurf1 results in accumulation of phosphorylated MEKK2 in osteoblasts and activation of its downstream JNK signaling cascade. Our results reveal a novel function of Smurf1 in the regulation of osteoblast physiology and bone homeostasis, and provide an interesting example for the importance of the mitogen-activated protein kinase (MAPK) signaling pathway in shaping specific biological response to the TGF-beta family of cytokines. Currently, we are characterizing the phenotypes of Smurf1 and Smurf2 double deficient mice to investigate how Smurf-mediated ubiquitination affects cell growth, tissue differentiation and other biological processes regulated by the TGF-beta family of ligands.

Although Smads are involved in most actions of the TGF-beta superfamily, activated TGF-beta receptors also transduce signals through other intracellular signaling pathways, especially those mediated by MAP kinases. The second area of research of our research focuses on the specific mechanism by which TGF-beta receptors activate MAP kinases independent of Smads, and the biological significance of this non-Smad dependent pathway in TGF-beta signaling. Previously, we have generated a mutant TGF-beta type I receptor that is unable to activate Smads but retains kinase activity. We found that this mutant TGF-beta type I receptor is able to activate p38 kinase, and the p38 activation is required for TGF-beta induced apoptosis and epithelial to mesenchymal transition. These results indicate that the TGF-beta receptor exerts its signals through multiple intracellular pathways and provide first hand biochemical evidence to support the existence of Smad-independent TGF-beta receptor signaling. Currently we are working to identify downstream mediators that are responsible for Smad-independent TGF-beta receptor signaling. These studies could uncover novel molecular mechanisms that account for a number of Smad-independent TGF-beta signaling responses.

The third direction of our research focuses on the effect of aberrant Smad signaling in tumorigenesis. We have generated different lines of transgenic mice carrying either wild type, or dominant negative or Smad3 under the control of a tetracycline-repressible promoter (tet-off). We crossed these mice to LAP-tTA mice, which allow tetracycline-regulated expression of tetracycline-transactivating protein (tTA) specifically in hepatocytes, to express Smad3 and its variants in liver. We find that elevated Smad3 expression protects liver from chemically induced carcinogenesis due to a heightened hepatic response to apoptotic stimuli. We plan to continue using this model to further explore the role of Smad3 in late stages of liver tumor progression and metastasis. Analysis of these Smad3 transgenic mice should advance our understanding of distinct physiological and pathological functions of this protein in cell proliferation, differentiation and tumorigenesis.

This page was last updated on 9/22/2008.